1,1′-Methylene-bis(1,1′,2,2′,3,3′,4, 4′-octahydroisoquinoline): Synthesis, reaction, resolution, and application in catalytic enantioselective transformations

Article abstract of DOI:10.1016/j.tet.2011.04.004

The preparation of new chiral 1,3-diamine ligand systems based on the 1,1′-methylene-bis(1,1′,2,2′,3,3′,4,4′- octahydroisoquinoline) framework is described. Synthesis of various mono-, di-, and bridged N-alkyl derivatives are presented. Resolution of one

Full text of DOI:10.1016/j.tet.2011.04.004

Tetrahedron 67 (2011) 4086e4092
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1,10-Methylene-bis(1,10,2,20,3,30,4,40-octahydroisoquinoline): synthesis, reaction,
resolution, and application in catalytic enantioselective transformations
*
Qiong Ji Yao, Zaher M.A. Judeh
School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, N1.2 B1-14, Singapore 637459, Singapore
a r t i c l e i n f o
a b s t r a c t
The preparation of new chiral 1,3-diamine ligand systems based on the 1,10-methylene-
bis(1,10,2,20,3,30,4,40-octahydroisoquinoline) framework is described. Synthesis of various mono-, di-, and
bridged N-alkyl derivatives are presented. Resolution of one compound, its Cu(I)Br X-ray crystallographic
structure and the preliminary results on its application in the enantioselective Henry and Aldol reactions
are disclosed.
Article history:
Received 20 January 2011
Received in revised form 15 March 2011
Accepted 4 April 2011
Available online 9 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bisisoquinoline
Chiral 1,3-diamines
CeC bond formation
Henry reaction
Aldol reaction
Copper bromide
1. Introduction
obtained suggesting great potential for further improvements.3b,4
Based upon our solution and solid state studies3a,c,d as well as
Application of chiral nitrogen ligands in the form of metal
complexes, auxiliaries and organocatalysts in various catalytic
asymmetric transformations is well documented.1 For example, the
privileged catalyst, salen has been extensively used in many
enantioselective reactions.2 We3 and others4 have been interested
in constructing chiral bidentate 1,10-bisisoquinolines, such as 1 and
2 (Fig. 1) and employing them as catalysts for various enantiose-
lective reactions. Moderate to very good selectivities have been
DFT calculations,5 we found that 1,10-bisisoquinolines assume dif-
ferent structural conformations depending upon the degree of
saturation of the heterocyclic ring (i.e., 1 vis 2, Fig. 1) as well as the
type (alkyl, acyl, sulfonyl) and steric bulkiness of the substituents
on the nitrogens. Additionally, the structural conformations were
found to have direct impact on the reactivity and selectivity in the
enantioselective addition of Et2Zn to aldehydes.3b Such a discovery,
combined with limited structural varieties of chiral 1,10-bisisoqui-
nolines, prompted us to search for more efficient 1,10-bisisoquino-
line ligands.
Without exceptions, to our knowledge, all the reported3,4a,b
reduced and partially reduced chiral 1,10-bisisoquinolines have
their two nitrogens in a 1,2-disposition (e.g., 1 and 2, Fig. 1) and
would form five-membered chelated rings after coordination with
metal ions. Considering the vital influence of the bite angle and the
conformational flexibility of the ligands on the reactivity and se-
lectivity, we envisaged that a new arrangement in which the two
nitrogens are 1,3-disposed (i.e., 1,3-diamine) to form six-membered
chelating rings (e.g., 3, Fig. 1), would bring a new conformation
different to those obtained with five-membered chelated ring as in
the case of 1 and 2. In anticipation of doing so, this would be the
first time that the framework 3 has been applied in asymmetric
catalysis.
H
H
H
H
NH
NH
N
NH
NH
NH
H
2
1
3
C -symmetric
1,2 nitrogens
C -symmetric
1,3 nitrogens
C -symmetric
1,2 nitrogens
2
2
1
Fig. 1. Structures of 1,10-bisisoquinolines.
Herein, we report on the chemistry of 1,10-methylene-
* Corresponding author. Fax: þ65 67947553; e-mail address: zaher@ntu.edu.sg
bis(1,10,2,20,3,30,4,40-octahydroisoquinoline)
3
including
its
(Z.M.A. Judeh).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.004

Q.J. Yao, Z.M.A. Judeh / Tetrahedron 67 (2011) 4086e4092
4087
synthesis, reactivity, resolution, and its complexation with CuBr.
Preliminary results on the application of 3 in the enantioselective
Henry and Aldol reactions will also be presented.
reactions, these derivatives would be expected to exhibit differing
selectivities and reactivities since they possess contrasting effects:
the symmetric ligands will maintain the C2-symmetry and possess
similar sp3 nitrogens having the same basicity while the unsym-
metric ligands will possess C2-symmetry and two electronically
different sp3 nitrogens (alkylated and none alkylated nitrogens)
having diverse basicities. Such contrasting effects are important to
add variety to the framework of rac-3 and distinguish between the
two nitrogens especially in the chelated state since the Lewis
acidity/basicity directly impact ligands selectivities and re-
activities.7 Thus, rac-3 was subjected to standard alkylation con-
ditions using suitable alkyl halides to produce the doubly N-alkyl
ligands rac-8e10.8 Reaction between rac-3 and neat iodomethane
followed by treatment with aqueous NaOH gave the desired
product rac-8 (Scheme 2). Reaction between rac-3 and both ethyl
bromide and benzyl bromide in the presence of K2CO3 gave rac-9
and 10, respectively, in excellent yields (Scheme 2).
2. Results and discussion
2.1. Preparation of rac-1,10-methylene-1,10,2,20,3,30,4,40-
octahydrobisisoquinoline
We and others have exploited BischlereNapieralski reaction
successfully for the synthesis of a wide range of 1,10-bis(3,30,4,40-
tetrahydroisoquinoline) compounds using various dehydrating
agents.3aee,4a,6aee Building on our experience in this area, we chose
to synthesize 3 as shown in Scheme 1. Reaction between phene-
thylamine 4 and diethyl malonate gave bisamide 5, which upon
cyclization using POCl3/P2O5 as dehydrating agents gave compound
6.6d,e Earlier studies on the reduction of similar 1,10-bis(3,30,4,40-
tetrahydroisoquinoline) compounds, where C1 and C10 are directly
connected, using NaBH4 gave mixtures of racemic and meso 1,10-
bis(1,10,2,20,3,30,4,40-octahydroisoquinoline) compounds while re-
duction of the same using NaCNBH3 gave only racemic isomer-
s.3c,6a,c Therefore, we chose to reduce 6 using NaCNBH3 in
anticipation of obtaining the desired rac-3 (Scheme 1).6a
N
N
NH
NH
N
N
iii
73%
i, ii
41%
rac-8
rac-3
93%
rac-9
O
O
HN
HN
i
ii
iv
NH2
89%
81%
4
N
5
N
N
N
NH
NH
iii, iv
rac-10
77%
Reagent and conditions: i) neat CH3I, 12 h; ii) NaOH, H2O, CH2Cl2;
iii) 2.2 equiv ethyl bromide, K2CO3, THF, 60 oC, overnight; iv) 2.2
equiv benzyl bromide, K2CO3, THF, 60 oC, overnight
6
rac-3
Reagents and conditions: i) (EtOCO)2CH2, 80 oC, 2
days; ii) POCl3, P2O5, toluene, reflux, 24 h; iii)
NaCNBH3, MeOH, HCl, 0.5 h; iv) NaOH, H2O, CH2Cl2
Scheme 2. Synthesis of doubly N-alkyls rac-8e10.
Attempts to directly prepare mono N-alkyl derivatives by
treatment of rac-3 with 1 mol of ethyl or benzyl bromides, failed to
produce the desired mono N-alkylated products. Instead, mixtures
of mono N-alkylated, doubly N-alkylated products were obtained
along with the starting material rac-3 thus indicating that the
second alkylation step (to form the doubly N-alkylated products) is
faster than the first one (which forms the mono N-alkylated
products). To overcome this problem, we adapted the sequence of
aminal formation followed by reduction.8b Therefore, condensation
of rac-3 with formaldehyde, acetaldehyde, and benzaldehyde gave
aminals rac-7, rac-11, and rac-12, respectively, which upon re-
duction using NaCNBH3 gave the required corresponding mono
N-alkylated derivatives rac-13, rac-14, and rac-15, respectively, in
very good overall yields (Scheme 3).
Scheme 1. Synthesis of rac-3.
Reduction of 6 with NaCNBH3 gave single isomer 3 whose ste-
reochemistry needed to be established since one of the main ob-
jectives of this work was to obtain 3 in enantiopure form for
application in asymmetric catalysis. Therefore, we synthesized (see
later) formaldehyde adduct 7 and examined its 1H NMR spectrum
focusing on the NeCH2eN0 protons. If 3 is racemic, the NeCH2eN0
protons should appear as a singlet since they are in a similar en-
vironment with respect to the lone pair electrons on the adjacent
nitrogens.6c Indeed, we were delighted to see
a
singlet at
d
3.84 ppm corresponding to the NeCH2eN0 protons confirming
the racemic nature of 3. In a meso-3 isomer, the NeCH2eN0 proton
signals would be split and appear as an AB quartet with two dif-
ferent chemical shifts.6c More evidence to the racemic nature of 3
comes from single X-ray crystallography discussed later.
2.3. Resolution of rac-1,10-methylene-bis(1,10,2,20,3,30,4,40-
octahydroisoquinoline) rac-3
2.2. Alkylation of rac-1,10-methylene-bis(1,10,2,20,3,30,4,40-
octahydroisoquinoline) rac-3
We required access to enantiopure 3 for further enantioselective
catalysis studies. After a survey of different chiral acids, we found
that the salt of rac-3 and (
L
)-(þ)-citramalic acid (2 equiv) crystal-
Having established the racemic nature of 3, we set to prepare
both its symmetric and unsymmetric derivatives through alkyl-
ation of the nitrogens. Once used as ligands in enantioselective
lizes in a mixture of H2O and EtOH (1:1.5, v:v) to give enantiopure
and highly enriched batches of crystals upon standing at rt. The
enantiopure batches were treated separately with 10% NaOH and

4088
Q.J. Yao, Z.M.A. Judeh / Tetrahedron 67 (2011) 4086e4092
R
H
% yield
85
logical to use this reaction as a test-bed to examine the effectiveness
of (R,R)-3. Our preliminary results indicated that the addition of
nitromethane (20 equiv) to benzaldehyde 17 in the presence of
10 mol % (R,R)-3 and 10 mol % CuBr gave the desired product (S)-18
in 70% yield and 38% ee (Scheme 4).
rac-7
NH
NH
N
N
NH
R
ii
i
rac-11 CH3
rac-12 Ph
80
90
R'
H
N
R'
% yield
72
rac-13 CH3
rac-3
rac-13-15
rac-7,11-12
rac-14 CH2CH3 70
The stereochemical observation of the product in Scheme 4 can
be explained based on the reaction mechanism shown in Fig. 3. The
nitro group is known to strongly coordinate to soft metals.13 Thus,
nitomethane is activated and deprotonated to generate the active
nitronate nucleophile on the (R,R)-3/Cu(I) complex.7,13 The nitro-
nate group assumes an axial position in Fig. 3 with the help of the
hydrogen bonding between the nitro group and the sp3-NeH.
Subsequent coordination of the benzaldehyde in such a way that it
occupies the outside position by appropriately orienting itself in
such a way to avoid steric hindrance with the isoquinoline ring
results in formation of a tetracoordinated Cu(I) transition state
which favors the Re face nucleophilic attack of the nitronate on the
benzaldehyde carbonyl to give the corresponding (S)-18 (Fig. 3).
rac-15 CH2Ph
78
Reagents and conditions: i) RCHO, EtOH, 4A
molecular sieve; ii) NaCNBH3, HCl, MeOH.
Scheme 3. Synthesis of aminals rac-7, rac-11, and rac-12 and mono N-alkyls rac-13e15.
extracted with CH2Cl2 to give the (ꢀ)-3 and (þ)-3 enantiomeric
products. The enantiomeric purities of (ꢀ)-3 and (þ)-3 were con-
firmed by chiral HPLC and were found to be >99%. Crystallization of
a mixture of (þ)-3 and ( )-(þ)-citramalic acid from EtOH produced
L
colorless cubic crystals suitable for single X-ray crystallographic
analysis.9 The crystal structure of the salt of (þ)-3 (Fig. 2) proved
that (i) (þ)-3 has the (R,R) absolute configuration and consequently
Fig. 2. ORTEP diagrams of (a) (R,R)-3 and (b) rac-3/CuBr complex 16.
(ꢀ)-3 should have the (S,S) absolute configuration; and (ii) re-
duction of 6 using NaBH3CN produced rac-3 (Scheme 1).
We were delighted to obtain single crystals suitable for X-ray
crystallographic analysis when a methanolic solution of rac-3 and
CuBr was allowed to crystallize at rt. The X-ray structure of the rac-
3/CuBr complex 16 demonstrated a mononuclear six-membered
chelated ring (Fig. 2).10
OH
O
i
NO2
MeNO2
+
Ph
Ph
H
(S)
70% yield
38% ee
(20 equ.)
17
(S)-18
Reagents and conditions: i) 10 mol% (R,R)-3, 10 mol%
CuBr, dioxane, r.t., 40 h.
Scheme 4. Enantioselective addition of nitromethane to benzaldehyde 17 using (R,R)-3.
2.4. Application of (R,R)-3 in catalytic enantioselective Henry
and Aldol reactions
OH
O
O
O
+
i
With the chiral diamine (R,R)-3 in hand, we then examined its
ability to catalyze the enantioselective Henry (Scheme 4) and Aldol
(Scheme 5) reactions.
(S)
H
37% yield
70% ee
O2N
O2N
Henry reaction is a very powerful CeC bond-forming tool in or-
ganic synthesis. The resultant nitroalcohol adducts can be trans-
formed using well documented protocols into many important
building blocks, such as nitroalkenes, amino alcohols, and amino
acids etc.11 Chiral diamine/copper complexes have been reported as
catalysts for this reaction with variable success.12 Therefore, it was
19
(S)-20
Reagents and conditions: 20 mol% (R,R)-3,
20 mol% PTSA, acetone, r.t., 4 d.
Scheme 5. Enantioselective addition of acetone to 4-nitrobenzaldehyde 19 catalyzed
by (R,R)-3.

Q.J. Yao, Z.M.A. Judeh / Tetrahedron 67 (2011) 4086e4092
4089
were recorded on Agilent LC system with Agilent Mass selective
detector. Optical rotation values were measured using JASCO P-
1020 polarimeter.
O
H
H
N
O
N
N
N
N
Br
Br
O
Cu
Cu
H
H
4.2. Preparation of N,N0-bisphenethylmalonamide 5
N
O
Diethyl malonate (3.2 mL, 0.021 mol) was added dropwise over
a period of 10 min to phenethylamine (5.2 mL, 0.042 mol) and the
mixture was vigorously stirred at 80 ꢁC for 2 days whereby thick
yellow solid was obtained. After reaction completion (TLC analysis),
the yellow solid was transferred to a Buckner funnel, washed with
hexane (3ꢂ10 mL), and dried in a dissector. N,N0-Bisphenethylma-
lonamide 5 was obtained as a fluffy white solid (5.8 g, 89%), mp
102e104 ꢁC. FTIR (KBr) nmax: 3298, 1659, 1633, 1548, 1229, 747, 698,
OH
NO2
+ HBr
-HBr
O
(S)
Ph
H
N
N
H
N
Cu
O
O
Cu
N
H
O
N
575 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
: 2.82 (4H, t, J¼7.2 Hz), 3.04
Ph Re
H
O
H
O
C
N
h
P
(2H, s), 4.16 (4H, t, J¼7.2 Hz), 6.93 (2H, br s), 7.17e7.56 (10H, m). 13C
H
NMR (75.6 MHz, CDCl3) d: 35.5, 40.9, 43.2, 126.6, 128.6, 128.7, 138.6,
167.2. m/z (ESI): calcd for C19H22N2O2: 310, found 311 (Mþ1).
Fig. 3. Proposed mechanism for the asymmetric Henry reaction catalyzed by (R,R)-3/
CuBr complex.
4.3. Preparation of 1,10-methylene-bis(3,30,4,40-
tetrahydroisoquinoline) 6
Additionally, the enantioselective Aldol14 reaction between 4-
nitrobenzaldehyde 19 and acetone in the presence of (R,R)-3 and p-
toluenesulfonic acid (PTSA) was also examined briefly. The desired
aldol product (S)-20 was obtained smoothly in 37% yield and 70% ee
(Scheme 5).
While a wide range of conditions have not been evaluated in
both the Henry and Aldol reactions, the fact that 38% ee and 70% ee,
respectively, were obtained using ligand (R,R)-3 is very promising
and suggests great potential for development and optimization.
POCl3 (3.66 mL, 0.04 mol) was added dropwise to a stirred
cooled (ice bath) suspension of N,N0-bisphenethylmalonamide 5
(1.34 g, 0.004 mol) and P2O5 (5.7 g, 0.04 mol) in toluene (15 mL).
After complete addition, the ice bath was removed and the mixture
was heated under reflux overnight. The reaction mixture was then
cooled to rt, the solvent was decanted and saturated NaHCO3 so-
lution (20 mL) was added to the remaining yellow solid until gas
evolution was no longer observed. Saturated NaOH (25 mL) was
then added to adjust the pH of the mixture to pH 11. The alkaline
solution was extracted with CH2Cl2 (4ꢂ30 mL) and the combined
organic extracts were washed with brine, dried over MgSO4, and
the solvent was evaporated under reduced pressure. The resulting
dark brown gum was purified by column chromatography to give
1,10-methylene-3,30,4,40-tetrahydrobisisoquinoline 6 as a brown
gum (0.89 g, 81%). FTIR (KBr) nmax: 1618, 1311, 1272, 1232, 1029,
3. Conclusion
We have successfully achieved the synthesis of a new ligand
framework, the 1,10-methylene-bis(1,10,2,20,3,30,4,40-octahydroiso-
quinoline) 3 and prepared its symmetric and unsymmetric ligands
through the synthesis of various mono-, di-, and bridged N-alkyls.
The absolute stereochemistry of the new framework was estab-
lished through X-ray crystallography for the first time. Metal
complexation with Cu(I)Br revealed the formation of mononuclear
complex. Preliminary results on application of (R,R)-3 in the
enantioselective Henry and Aldol reaction were very promising and
warrant further investigations. Optimization of the reaction con-
ditions and further applications in other asymmetric reactions of
the new ligands are still in progress in our laboratory and will be
reported in due course.
746 cmꢀ1. 1H NMR (300 MHz, CDCl3)
(4H, t, J¼6.9 Hz), 5.93 (1H, s), 7.17e7.19 (2H, m), 7.25e7.35 (4H, m),
7.72e7.77 (2H, m). 13C NMR (75.6 MHz, CDCl3)
: 28.5, 42.4, 84.9,
d
: 2.80 (4H, t, J¼6.6 Hz), 3.60
d
124.6, 126.7, 127.8, 129.2, 131.5, 137.2, 157.8. HRMS (ESI): found
(Mþ1) 275.1553. C19H18N2þH requires 275.1548.
4.4. Preparation of rac-1,10-methylene-bis(1,10,2,20,3,30,4,40-
octahydroisoquinoline) rac-3
1,10-Methylene-bis(3,30,4,40-tetrahydroisoquinoline)
6 (0.89 g,
3.25 mmol) was dissolved into 0.5 M HCl/MeOH solution (10 mL)
and the resulting brown solution was evaporated to give a gummy
brown residue. The residue was redissolved in MeOH (6 mL) and
the resultant dark brown solution was added over 5 min to a stirred
suspension of NaCNBH3 (0.35 g, 5.52 mmol) in a mixture of MeOH
(8 mL) and 3% HCL-MeOH (2 mL) at rt. After complete addition, the
mixture was kept stirring for another 0.5 h. The solvent was then
removed under reduced pressure until almost dry. NaOH solution
(20 mL, 10%) was added to bring the solution to pH 11. The alkaline
solution was then extracted with CH2Cl2 (how much 3ꢂ15 mL). The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and the filtrates were evaporated under reduced
pressure to give brown solid that was recrystallized from EtOH to
4. Experimental section
4.1. General remarks
All chemicals were reagent grade unless otherwise specified.
Analytical thin layer chromatography (TLC) was performed using
Merck 60 F254 precoated silica gel plates (0.2 mm thickness).
Products separation was achieved on Merck Silica Gel 60
(230e400 mesh) using column chromatography. Melting points
were determined on Bamstead Electrothermal 9100 melting point
tester. FTIR spectra were recorded on PerkineElmer FTIR system
Spectrum BX. 1H (300 MHz) and 13C (75.47 MHz) NMR spectra were
recorded on a Bruker Advanced DPX 300 spectrometer with TMS as
internal reference. High resolution mass spectra were recorded on
give
rac-1,10-methylene-bis(1,10,2,20,3,30,4,40-octahydroisoquino-
line) rac-3 (0.70 g, 77%), mp 98e102 ꢁC. FTIR (KBr) nmax: 3325, 3249,
Finigan MAT 95
*
P spectrometer. X-single crystal diffraction data
2923, 2853,1497,1453,1127, 866, 767, 702 cmꢀ1. 1H NMR (300 MHz,
were obtained on Bruker-AXS Smart Apex CCD single-crystal dif-
fractometer. HPLC separation was performed on Agilent 1100 using
Diacel Chiralcel OD-H and AS-H chiral columns. LCeMass spectra
CDCl3)
d
: 2.19 (2H, t, J¼6.6 Hz), 2.46 (2H, br s), 2.63e2.72 (2H, m),
2.76e2.85 (2H, m), 2.91e2.99 (2H, m), 3.18e3.26 (2H, m), 4.17 (2H,
t, J¼6.6 Hz), 6.99e7.10 (8H, m). 13C NMR (75.6 MHz, CDCl3)
d: 30.0,

4090
Q.J. Yao, Z.M.A. Judeh / Tetrahedron 67 (2011) 4086e4092
40.9, 42.0, 52.9, 125.8, 125.9, 126.0, 129.4, 135.5, 139.7. HRMS (ESI):
found 279.1855 (Mþ1). C19H22N2þH requires 279.1861.
m), 3.02e3.20 (4H, m), 3.36e3.42 (2H, m), 4.13 (2H, t, J¼6.6 Hz),
7.08e7.16 (8H, m).13C NMR (75.6 MHz, CDCl3)
: 13.8, 22.3, 41.5, 46.0,
46.9, 57.8, 125.4, 125.7, 128.4, 128.8, 134.4, 139.8. HRMS (ESI): found
d
4.5. Resolution of rac-3 with (L)-(D)-citramalic acid
(Mþ1) 335.2477. C23H30N2þH requires 335.2487.
(L)-(þ)-Citramalic acid (1.04 g, 7.0 mmol) was added to a solu-
4.6.3. N,N0-Dibenzyl-1,10-methylene-bis(1,10,2,20,3,30,4,40-octahy-
droisoquinoline) rac-10. Compound rac-3 (560 mg, 2 mmol) was
tion of rac-3 (1.0 g, 3.5 mmol) in EtOH/H2O (1.5:1, 15 mL) and stir-
red for 15 min at 40 ꢁC. The resulting solution was left undisturbed
at rt for several days where six crystalline batches were harvested.
The first two batches of crystals were combined and suspended in
CH2Cl2 (6 mL). NaOH solution (10 mL, 10%) was added to make the
pH 11. The layers were separated and the aqueous layer was further
extracted with CH2Cl2 (3ꢂ6 mL). The combined organic layers were
dried over MgSO4, filtered, and the filtrate evaporated under re-
duced pressure to give (S,S)-3 as a light yellow solid (150 mg, 15%,
>99% ee). The next three batches of crystals were treated in
a similar manner to the first two batches to give 3 (240 mg, 24%,
(S,S)-3 was obtained as enriched product in 70e80% ee). The sixth
batch of crystals was processed similarly to give (R,R)-3 as a white
solid (30 mg, 3%, >99% ee). The mother liquor was evaporated to
give white solid that was also processed similarly as described for
the above batches to give (R,R)-3 (540 mg, 54%, 40% ee). The ees of
enantiomers were determined by HPLC (Daicel Chiralcel OD-H
column), hexane/i-PrOH/Et3N¼90/9.9/0.1, 1.0 mL/min, 256 nm,
treated with benzyl bromide (523 ml, 4.4 mmol, 2.2 equiv) as de-
scribed in the general procedure. Purification of the product using
silica gel column chromatography (EtOAc/Hex, 1:10) gave N,N0-
dibenzyl-1,10-methylene-1,10,2,20,3,30,4,40-octahydrobisisoquinoline
rac-10 as a light yellow solid (852 mg, 93%), mp 159e161 ꢁC. FTIR
(KBr) nmax: 2951, 2818, 1493, 1450, 1346, 1097, 1023, 744, 698 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
d
: 1.87 (2H, apparent t, J¼6.6 Hz), 2.27
(1H, d, J¼4.0 Hz), 2.33 (1H, d, J¼4.5 Hz), 2.82 (2H, dd, J¼12.0, 6.0 Hz),
2.91e2.98 (2H, m), 3.13e3.19 (2H, m), 3.40 (2H, d, J¼13.2 Hz), 3.66
(2H, d, J¼12.9 Hz), 4.02 (2H, t, J¼6.9 Hz), 6.96e7.23 (9H, m). 13C NMR
(75.6 MHz, CDCl3) d: 22.2, 40.7, 46.9, 57.5, 59.2, 125.6, 126.0, 126.9,
128.2, 128.3, 129.0, 129.1, 134.3, 139.7, 140.1. HRMS (ESI): found
459.2808 (Mþ1). C33H34N2þH requires 459.2800.
4.7. Preparation of mono N-substituted rac-3 derivatives
4.7.1. Condensation of rac-3 with aldehydes. General procedure: The
aldehyde (2.7 mmol) was added dropwise or portionwise (for solids)
to a stirred solution of rac-3 (560 mg, 2 mmol) in EtOH or Et2O
(10 mL) at rt. Stirring of the resultant reaction mixture was continued
at rt or heated to reflux for a specific time (TLC). After the reaction
completion, the mixture was filtered through Celite and the filtrates
evaporated to dryness. The residue was then purified by column
chromatography on silica gel to afford the piperimidine products.
t1¼12.12 min for (R,R)-3, t2¼17.72 min for (S,S)-3. For (R,R)-3, ½a D25
ꢃ
þ20.53 (c 1.00, CHCl3). For (S,S)-3, ½a D25
ꢃ ꢀ22.94 (c 1.01, CHCl3).
4.6. Preparation of double N-substituted rac-3 derivatives
General procedure: Alkyl bromide or alkyl iodide (4.4 mmol) was
added to a mixture of rac-3 (2 mmol) and K2CO3 (4.4 mmol) in THF
(8 mL). The mixture was stirred and heated at reflux for overnight.
The reaction mixture was then cooled to rt, filtered and the solid
was washed with CH2Cl2. The combined organic filtrates were
evaporated to dryness. The residue was recrystallized from EtOH or
subjected to column chromatography on silica gel to give the
double N-substituted derivatives.
4.7.2. Reaction with formaldehyde. Reaction between rac-3
(560 mg, 2 mmol) and 37% formaldehyde (205 ml, 2.7 mmol,
methanol solution) in EtOH at reflux for 2 days, according to the
general procedure, afforded a yellow solid. Purification by chro-
matography on silica gel (EtOAc/Hex, 1:1) gave piperimidine rac-7
as a light yellow solid (490 mg, 85%), mp 116e119 ꢁC. FTIR (KBr)
4.6.1. N,N0-Dimethyl-1,10-methylene-bis(1,10,2,20,3,30,4,40-octahy-
droisoquinoline) rac-8. Compound rac-3 (560 mg, 2 mmol) was stir-
red in neat iodomethane (5 mL) at 50 ꢁC for 5 h. The volatiles were
removed under reduced pressure to give a yellow gum. A mixture of
5 M NaOH (15 mL) and CH2Cl2 (15 mL) was added to the gum and the
mixture formed was then stirred for 2 h at rt. The organic phase was
separated, dried over NaOH (pellets), filtered, and evaporated to
dryness. The resulting yellow solid was recrystallized from EtOH to
give N,N0-dimethyl-1,10-methylene-1,10,2,20,3,30,4,40-octahydrobisiso-
quinoline rac-8 as light yellow crystals (245 mg, 41%), mp
106e109 ꢁC. FTIR (KBr) nmax: 2924, 1448, 1378, 1284, 1116, 1031, 775,
nmax: 1492, 1454, 1361, 1287, 1156, 1093, 1026, 750 cmꢀ1
.
1H NMR
: 2.57 (2H, t, J¼5.7 Hz), 2.68e2.75 (2H, m),
2.91e3.15 (4H, m), 3.24e3.31 (2H, m), 3.73 (2H, s), 3.90e4.05 (2H,
m), 6.99e7.15 (8H, m). 13C NMR (75.6 MHz, CDCl3)
: 26.6, 32.0, 47.7,
(300 MHz, CDCl3)
d
d
55.6, 69.7, 125.6, 126.3, 126.3, 129.3, 134.9, 136.8. HRMS (ESI): found
(Mþ1) 291.1860. C20H22N2þH requires 291.1861.
4.7.3. Reaction with acetaldehyde. Reaction between rac-3 (560 mg,
2 mmol) and acetaldehyde (151 ml, 2.7 mmol) in Et2O at rt overnight,
according to the general procedure, gave a yellow gum. Purification
of the gum using silica gel column chromatographic (EtOAc) gave
piperimidine rac-11 as a light yellow gum (483 mg, 80%). FTIR (KBr)
nmax: 1490,1452,1376,1161,1074,1032, 746 cmꢀ1. 1H NMR (300 MHz,
743, 609 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d: 1.84 (2H, apparent t,
J¼7.2 Hz), 2.41 (1H, d, J¼6 Hz), 2.46 (1H, d, J¼5.7 Hz), 2.51 (6H, s),
2.88e3.05 (4H, m), 3.27e3.36 (2H, m), 3.91 (2H, t, J¼6.6 Hz),
CDCl3)
d
: 1.31 (3H, d, J¼6.0 Hz), 2.24e2.29 (1H, m), 2.41e2.46 (2H,
7.00e7.06 (8H, m). 13C NMR (75.6 MHz, CDCl3)
d: 22.5, 42.2, 44.5,
m), 2.74e2.97 (5H, m), 3.12e3.20 (1H, m), 3.27e3.29 (1H, m),
3.78e3.82 (1H, m), 3.90 (1H, q, J¼6 Hz), 4.30 (1H, br s), 6.90e7.17
45.9, 59.9, 125.5, 125.8, 128.3, 128.7, 134.0, 139.1. HRMS (ESI): found
(Mþ1) 307.2166. C21H26N2þH requires 307.2174.
(7H, m), 7.28 (1H, d, J¼7.2 Hz). 13C NMR (75.6 MHz, CDCl3)
d: 18.3,
23.8, 29.9, 31.8, 37.1, 47.2, 55.4, 57.1, 68.9, 125.6, 126.1, 126.3, 126.5,
126.7, 128.9, 129.4, 134.6, 135.9, 136.7, 139.2. HRMS (ESI) calcd for
C21H24N2: 304.2018, found 305.2019 (Mþ1).
4.6.2. N,N0-Diethyl-1,10-methylene- bis(1,10,2,20,3,30,4,40-octahydroiso-
quinoline) rac-9. Compound rac-3 (560 mg, 2 mmol) was treated
with bromoethane (360 ml, 4.4 mmol, 2.2 equiv) as described in
general procedure. Purification of the product using silica gel column
chromatography (EtOAc/Hex, 1:5) gave N,N0-diethyl-1,10-methylene-
1,10,2,20,3,30,4,40-octahydrobisisoquinoline rac-9 as light yellow solid
(490 mg, 73%), mp 118e121 ꢁC. FTIR (KBr) nmax: 2957, 1447, 1379,
4.7.4. Reaction with benzaldehyde. Reaction between rac-3
(560 mg, 2 mmol) and benzaldehyde (270 ml, 2.7 mmol) in Et2O at
rt overnight, according to the general procedure, gave yellow solid.
Purification of the solid by silica gel column chromatography
(EtOAc/Hex¼1:1) gave piperimidine 12 as a yellow fluffy solid
(483 mg, 90%), mp 73e76 ꢁC. FTIR (KBr) nmax: 1603, 1494, 1453,
1117, 1095, 1035, 768, 743, 616 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d:
1.24 (6H, t, J¼7.2 Hz), 1.97 (2H, apparent t, J¼6.6 Hz), 2.43 (1H, d,
J¼4.5 Hz), 2.49 (1H, d, J¼4.2 Hz), 2.66e2.73 (2H, m), 2.79e2.85 (2H,
1308, 1149, 1124, 1032, 842, 743 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d:

Q.J. Yao, Z.M.A. Judeh / Tetrahedron 67 (2011) 4086e4092
4091
2.14 (1H, td, J¼11.4, 3.6 Hz), 2.46e2.53 (3H, m), 2.62e2.74 (1H, m),
2.86e2.94 (3H, m), 3.08e3.17 (2H, m), 3.64 (1H, d, J¼11.1 Hz), 4.30
(1H, s), 4.64e4.72 (1H, m), 7.07 (1H, d, J¼7.5 Hz), 7.17e7.49 (10H,
(0.2 mmol, 1 equiv) were added sequentially. The reaction mixture
was further stirred at rt 40 h (TLC) and then subjected to column
chromatography on silica gel to give (S)-1-phenyl-2-nitroethanol 18
in 70% yield. HPLC analysis: (Chiralcel OD-H column) hexane/
IPA¼90/10, 0.8 mL/min, 215 nm, minor enantiomer t1¼18.10 min,
m), 7.62e7.65 (2H, m). 13C NMR (75.6 MHz, CDCl3)
d: 24.2, 29.8,
34.5, 46.5, 47.1, 56.1, 57.1, 80.8,124.9,125.6,125.8, 126.0,126.3,126.7,
128.39, 128.42, 128.8, 129.1, 129.2, 129.6, 129.8, 135.3, 135.7, 136.8,
138.5, 140.9. HRMS (ESI): found (Mþ1) 367.2158. C26H26N2þH re-
quires 367.2174.
major enantiomer t2¼22.20 min, 38% ee.15 1H NMR (CDCl3,
d ppm):
2.08e2.81 (1H, br s), 4.39e4.56 (2H, m), 5.37 (1H, dd, J¼12.6, 3.3 Hz),
7.34e7.40 (5H, m); 13C NMR: 71.0, 81.3,126.0,129.0,129.1, and 138.2.
4.7.5. Reductive cleavage of piperimidines rac-7, rac-11, and rac-
12. General procedure: A solution of the piperimidine (0.49 mmol) in
MeOH (1.8 mL) was added to a mixture of NaCNBH3 (47 mg,
4.9. Procedure for the asymmetric Aldol reaction
To a stirred mixture of (R,R)-3 (0.04 mmol, 20 mol %) and PTSA
(0.04 mmol, 20 mol %) in acetone (2.5 mL), 4-nitrobenzaldehyde 19
was added (0.2 mmol) dropwise at rt. The reaction mixture was
continuously stirred for 4 days and then subjected to silica gel
column chromatography purification to give (S)-4-hydroxy-4-(40-
nitrophenyl)-butan-2-one 20 in 37% yield. HPLC analysis: (Chir-
alpak AS-H column) hexane/IPA¼70/30, 1.0 mL/min, 254 nm, major
enantiomer t1¼10.76 min, major enantiomer t2¼13.24 min, 70%
0.75 mmol, 1.5 equiv) and TFA (154 ml, 2 mmol, 4 equiv) in MeOH
(3.5 mL) at 0 ꢁC. The mixture was stirred at rt for another 1 h. The
reaction was then quenched with 30% NaOH solution (10 mL) and
extracted with EtOAc (3ꢂ8 mL). The combined organic extracts were
dried over MgSO4, filtered, and the filtrates evaporated to dryness.
The crude product was purified by column chromatography over
silica gel (EtOAc) to give mono N-substituted derivatives rac-13e15.
ee.16 1H NMR (CDCl3,
d ppm): 2.19 (3H, s), 2.83e2.86 (2H, m), 3.91
4.7.5.1. Reductive cleavage of piperimidine rac-7. Piperimidine 7
(142 mg, 0.49 mmol) was treated as described in the general pro-
cedure to give N-methyl-1,10-methylene-bis(1,10,2,20,3,30,4,40-octa-
hydroisoquinoline) rac-13 as a light yellow gum (103 mg, 72%). FTIR
(KBr) nmax: 3300, 2930, 1675, 1452, 1373, 1200, 1125, 1068, 1026,
(1H, br s), 5.24e5.26 (1H, m), 7.51 (2H, d, J¼5.7 Hz), 8.13 (2H, d,
J¼5.7 Hz); 13C NMR: 30.7, 51.6, 68.8, 123.7, 126.5, 147.2, 150.3, and
208.5.
Acknowledgements
745 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d: 2.31e2.33 (2H, m),
2.46e2.47 (3H, m), 2.78e2.89 (6H, m), 3.01e3.32 (2H, m),
We gratefully acknowledge the Nanyang Technological Univer-
sity for financial support (Grant No. RG27/07), and also appreciate
scholarship support for Y.Q.J. from China Scholarship Council.
3.73e3.80 (1H, m), 4.08e4.19 (2H, m), 7.13e7.20 (8H, m). 13C NMR
(75.6 MHz, CDCl3) d: 24.7, 29.9, 40.5, 40.8, 42.2, 47.0, 53.8, 61.3,
125.8, 125.96, 125.99, 126.1, 126.2, 127.4, 128.9, 129.3, 134.7, 135.5,
137.7, 139.1. HRMS (ESI): found (Mþ1) 293.2021. C20H24N2þH re-
quires 293.2018.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.04.004.
4.7.5.2. Reductive cleavage of piperimidine rac-11. Piperimidine
rac-11 (150 mg, 0.49 mmol) was treated as described in the general
procedure to give N-ethyl-1,10-methylene-bis(1,10,2,20,3,30,4,40-
octahydroisoquinoline) rac-14 as a light yellow gum (105 mg, 70%).
FTIR (KBr) nmax: 3251, 2930, 1676, 1490, 1452, 1378, 1270,1200, 1118,
References and notes
1. For reviews see: (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev.
2003, 103, 2985e3012; (b) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102,
3129e3170; (c) Falorni, M. Trends Org. Chem. 1993, 4, 351e369; (d) Ager, D. J.;
Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835e875; (e) Waldmann, H.
Synlett 1995, 2, 133e141.
1034, 768, 744 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d: 0.92 (3H, t,
J¼7.2 Hz), 2.05e2.09 (1H, m), 2.16e2.21 (1H, m), 2.40e2.48 (3H, m),
2.65e2.85 (5H, m), 3.14e3.29 (2H, m), 3.70e3.73 (2H, m), 4.11 (1H,
2. Jacobsen, E. N.; Yoon, T. P. Science 2003, 299, 1691e1693 See also references
therein.
d, J¼7.8 Hz), 6.91e7.04 (8H, m). 13C NMR (75.6 MHz, CDCl3)
d: 13.4,
23.4, 30.1, 41.2, 41.4, 42.9, 47.0, 54.0, 58.0, 125.8, 125.9, 126.0, 126.0,
126.1, 127.8, 129.0, 129.3, 134.7, 135.7, 138.4, 139.4. HRMS (ESI):
found (Mþ1) 307.2168. C21H26N2þH requires 307.2174.
3. (a) Qi, G.; Yao, Q.-J.; Judeh, Z. M. A. Tetrahedron 2010, 66, 4195e4205; (b) Qi, G.;
Judeh, Z. M. A. Tetrahedron: Asymmetry 2010, 21, 429e436; (c) Busato, S.; Craig,
D. C.; Judeh, Z. M. A.; Read, R. W. Tetrahedron 2003, 59, 461e472; (d) Craig, D. C.;
Judeh, Z. M. A.; Read, R. W. Aust. J. Chem. 2002, 55, 733e736; (e) Judeh, Z. M. A.;
Ching, C. B.; McCluskey, A.; Bu, J. Tetrahedron Lett. 2002, 43, 5089e5091; (f)
Shen, H.-Y.; Ying, L.-Y.; Jiang, H.-L.; Judeh, Z. M. A. Int. J. Mol. Sci. 2007, 8,
505e512.
4.7.5.3. Reductive cleavage of piperimidine rac-12. Piperimidine
12 (180 mg, 0.49 mmol) was treated as described in general pro-
cedure to give N-benzyl-1,10-methylene-bis(1,10,2,20,3,30,4,40-octahy-
droisoquinoline) rac-15 as a light yellow gum (144 mg, 80%). FTIR
(KBr) nmax: 3340, 2930, 1651, 1490, 1453, 1360, 1201, 1118, 1023, 972,
4. (a) Cavell, K. J.; Elliott, M. C.; Nielsen, D. J.; Paine, J. S. Dalton Trans. 2006,
4922e4925; (b) Arai, S.; Takita, S.; Nishida, A. Eur. J. Org. Chem. 2005, 24,
5262e5267; (c) Seo, H.; Hirsch-Weil, D. K.; Abboud, A.; Hong, S. J. Org. Chem.
2008, 73, 1983e1986; (d) Baskakov, D.; Herrmann, W. A.; Herdtweck, E.;
Hoffmann, S. D. Organometallics 2007, 26, 626e632; (e) Herrmann, W. A.;
Baskakov, D.; Herdtweck, E.; Hoffmann, S. D.; Bunlaksananusorn, T.; Rampf, F.;
743, 699 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d: 1.97e2.05 (1H, m), 2.39
ꢀ
(1H, apparent t, J¼12 Hz), 2.62e2.70 (1H, m), 2.73e2.89 (4H, m),
3.05e3.12 (3H, m), 3.43e3.60 (1H, m), 3.69e3.81 (2H, m), 3.87 (1H,
dd, J¼11.1, 3.0 Hz), 4.30 (1H, d, J¼8.7 Hz), 7.08e7.21 (8H, m),
Rodefeld, L. Organometallics 2006, 25, 2449e2456; (f) Hrdina, R.; Dracínsky, M.;
ꢀ
ꢀ
Valterova, I.; Hodacova, J.; Císarova, I.; Kotora, M. Adv. Synth. Catal. 2008, 350,
1449e1456.
5. Xi, H.-W.; Judeh, Z. M. A.; Lim, K. H. J. Mol. Struct. 2009, 897, 22e31.
6. (a) Kuo, C.-Y.; Wu, M.-J.; Lin, C.-C. Eur. J. Med. Chem. 2010, 45, 55e62; (b)
Siegfried, M. A.; Hilpert, H.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1980, 63,
938e961; (c) Nielson, A. T. J. Org. Chem. 1970, 35, 2498e2503; (d) Fliedner, L. J.,
Jr.; Schor, J. M.; Myers, M. J.; Pachter, I. J. J. Med. Chem. 1971, 14, 580e583; (e)
Fancher, O. E.; Hayao, S.; Nichols, G. J. Am. Chem. Soc. 1958, 80, 1451e1456.
7. Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2003, 125, 12692e12693.
7.31e7.38 (5H, m). 13C NMR (75.6 MHz, CDCl3)
d: 23.0, 30.1, 41.4, 42.9,
43.3, 53.1, 56.8, 57.6, 125.8, 125.9, 126.0, 126.2, 126.3, 127.4, 128.2,
128.6, 129.3, 129.3, 129.4, 134.3, 135.5,138.3, 139.5, 139.6. HRMS (ESI):
found (Mþ1) 369.2328. C26H28N2þH requires 369.2331.
4.8. Procedure for the asymmetric Henry reaction
8. (a) Elliott, M. C.; Williams, E. Org. Biomol. Chem. 2003, 1, 3038e3047; (b) Chan,
K. H.; Deng, B.; Jones, M. W.; Read, R. W. Tetrahedron 2006, 62, 4979e4987.
9. X-ray crystallographic data for (R,R)-3$(L)-citramalic acid salt: Formula
(R,R)-3 (0.02 mmol, 10 mol %) and CuBr (0.02 mmol, 10 mol %)
were dissolved in dioxane (1.5 mL) and allowed to stir at rt for 1 h,
whereby a green solution was obtained. To the above stirred solu-
tion, nitromethane (4 mmol, 20 equiv) and benzaldehyde
ꢁ
C26.5H36N2O8.5, M¼518, tetragonal, space group P4(3)2(1)2, a¼11.7780 (3) A,
3
b¼11.7789 (3) A, c¼37.4305 (10) A,
b
¼90 , V¼5192.4(2) A , Dcalcd¼1.327 Mg/m3,
ꢁ
ꢁ
ꢁ
ꢁ
Z¼8.2.45ꢁ<
q
<31.07ꢁ. The number of reflections was 4798 considered to be
observed of 4139 unique data. Final R indices (I>2
s
(I)) R1¼0.0395, wR2¼0.0938.

4092
Q.J. Yao, Z.M.A. Judeh / Tetrahedron 67 (2011) 4086e4092
CCDC 800288 contains the supplementary crystallographic data for this paper.
This data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via http://www.ccdc.cam.ac.uk/.
43, 5442e5444; (c) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron:
Asymmetry 2006, 17, 3315e3326; (d) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J.
Org. Chem. 2007, 2561e2574.
10. X-ray crystallographic data for rac-3/Cu(I)Br complex: Formula C19H22BrCuN2,
13. Qin, B.; Xiao, X.; Liu, X.; Huang, J.; Wen, Y.; Feng, X. J. Org. Chem. 2007, 72,
9323e9328.
ꢁ
ꢁ
M¼422, triclinic, space group Pꢀ1, a¼8.9034 (2) A, b¼8.9512(2) A, c¼11.
3
ꢁ
ꢁ
4646(2) A,
85ꢁ<
b
¼103.6100(10)ꢁ, V¼854.84(3) A , Dcalcd¼1.639 Mg/m3, Z¼2.1.
14. For recent reviews, see: (a) Palomo, C.; Oiarbide, J.; Garcia, M. Chem. Soc. Rev.
2004, 33, 65e75; (b) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, Germany, 2004; Vol. 2; (c) List, B. Chem. Commun. 2006, 819e824;
(d) Figueiredo, R. M.; Christmann, M. Eur. J. Org. Chem. 2007, 2575e2600; (e)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471e5569; (f) Pellissier, H. Tetrahedron 2007, 63, 9267e9331; (g) Guillena, G.;
q
<31.18ꢁ. The number of reflections was 5542 considered to be observed
of 4626 unique data. Final R indices (I>2
s
(I)) R1¼0.0396, wR2¼0.0953. CCDC
800289 contains the supplementary crystallographic data for this paper. This
data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/.
ꢀ
ꢀ
11. (a) Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249e2293; (h)
Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles 2008, 75, 493e529; (i)
Mlynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502e1511; (j) Raj, M.;
Singh, V. K. Chem. Commun. 2009, 6687e6703; (k) Gruttadauria, M.; Giacalone,
F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33e57.
€
Pergamon: New York, NY,1991; Vol. 2, pp 321e340; (b) Shibasaki, M.; Groer, H. In
ComprehensiveAsymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Velag: Berlin, Heidelberg, Berlin,1999; Vol. III, pp 1075e1090; (c) Luzzio,
F. A. Tetrahedron 2001, 57, 915e945; (d) Ono, N. The Nitro Group in Organic Syn-
thesis; Wiley-VCH: New York, NY, 2001.
15. Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem.
12. For recent reviews on the catalytic asymmetric Henry reaction, see: (a) Mar-
ques-Lopez, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org. Chem. 2009, 15,
2401e2420; (b) Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004,
Commun. 2007, 616e618.
16. Chen, J.-R.; An, X.-L.; Zhu, X.-Y.; Wang, X.-F.; Xiao, W.-J. J. Org. Chem. 2008, 73,
6006e6009.